The term “angiogenesis” (also referred to as “neovascularization’) is a general term used to denote the growth of new blood vessels both in normal and pathological conditions.
Angiogenesis is an important natural process that occurs during embryogenesis, fetal and post-natal growth and in the adult healthy body in the process of wound healing, and in restoration of blood flow back into injured tissues. In females, angiogenesis also occurs during the monthly reproductive cycle to build up the uterus lining and to support maturation of oocytes during ovulation, and in pregnancy when the placenta is formed, in the process of the establishment of circulation between the mother and the fetus.
In the therapeutic field, there has been in recent years a growing interest in the control of angiogenesis. In one aspect, the aim was to control or diminish excessive and pathological angiogenesis that occurs in diseases such as cancer, diabetic blindness, age related macular degeneration, rheumatoid arthritis, psoriasis, and additional conditions. In these pathological conditions the new blood vessels feed the diseased tissue, for example the tumor tissue, providing it with essential oxygen and nutrients thus enabling its pathological growth. In addition, the pathological angiogenesis may destroy the normal tissue. Furthermore, the new blood vessels, formed for example in the tumor tissue, enable the tumor cells to escape into the circulation and metastasize in other organs.
Typically, excessive angiogenesis occurs when diseased cells produce abnormal amounts of angiogenetic growth factors, overwhelming the effect of the natural angiogenesis inhibitors present in the body.
Anti-angiogenetic therapies developed recently, are aimed at preventing new blood vessel growth through the targeting and neutralization of any of the stimulators that encourage the formation of new blood vessels.
A contrasting indication of regulating angiogenesis is the stimulation of production of neovascularization in conditions where insufficient angiogenesis occurs. Typically, these conditions are diseases such as coronary artery diseases, stroke, and delayed wound healing (for example in ulcer lesions). In these conditions, when adequate blood vessels growth and circulation is not properly restored, there is a risk for tissue death due to insufficient blood flow. Typically, insufficient angiogenesis occurs when the tissues do not produce adequate amounts of angiogenetic growth-factors, and therapeutic angiogenesis is aimed at stimulating new blood vessels' growth by the use of growth factors or their mimics.
The main goal of the angiogenesis therapy is to produce a biobypass—i.e., to physically bypass diseased or blocked arteries, by stimulating the body into building new blood vessels.
Tie2 is a receptor tyrosine-kinase for the endothelium growth factor angiopoietin 2. Its expression is mainly restricted to endothelial cells. Tie2 has been shown to be involved in tumor related angiogenesis and the use of modulators of Tie2 has been proposed in, for example, WO2004/006862, WO02/060382, WO01/44460 and WO00/18437.
Nevertheless there is a continuing need to provide treatments for disorders associated with excessive angiogenesis or for promoting new blood vessel growth. The present invention seeks to provide such a solution.
In addition, there is a need to provide a way of monitoring the extent of ongoing angiogenesis in a patient, particularly a patient undergoing treatment. The present invention seeks to provide such a method.